AB1694 IN VIVO MEASUREMENT OF POTENT AND DURABLE HUMAN ADIPOSE 11Β-HYDROXYSTEROID DEHYDROGENASE TYPE 1 INHIBITION BY SPI-62
Authors: D. Katz, G. An, C. Schmicker, B. Engel, T. Magers, R. Basu, J. Gutierrez
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> 11β-hydroxysteroid dehydrogenase type 1 (HSD-1), an intracellular enzyme that converts glucocorticoids (GC) from inactive (e.g., prednisone, cortisone) to active (e.g., prednisolone, cortisol) form is a main source of intracellular GC that can bind to intracellular GC, mineralocorticoid, and non-genomic receptors. Prior clinical and non-clinical results support the hypothesis that HSD-1 inhibitors have potential to mitigate GC toxicity without eliminating GC efficacy. Results from tissue-specific HSD-1 knockout mouse studies indicate that adipose is a key target tissue for GC cardiometabolic toxicity prevention or reversal. However, several HSD-1 inhibitors have shown tachyphylaxis on adipose inhibition in human within 14 days of dosing. <h3>Objectives</h3> Learn whether SPI-62 achieves full and durable adipose HSD-1 inhibition in human. <h3>Methods</h3> Participants with type 2 diabetes and BMI 30-45 kg/m<sup>2</sup> received SPI-62 daily for up to 14 days in an open label Phase 1 clinical trial. Microdialysis catheters (Type 63, µ dialysis, Stockholm Sweden) inserted in subcutaneous abdominal adipose were infused continuously with [2,2,4,6,6,9,12,12-<sup>2</sup>H<sub>8</sub>]cortisone (D8E) 1 µg/mL at 1 µL/min. Following selected SPI-62 doses, dialysate samples were collected at 0-2, 2-4, 4-6, 6-8, 8-10, 20-22, and 22-24 hours. D8E and [2,2,4,6,6,9,12,12-<sup>2</sup>H<sub>8</sub>]cortisol (D8F) concentrations in dialysate were measured using a validated LC-MS/MS assay. D8E results below the limit of quantitation (LOQ = 0.100 ng/mL) were imputed as the LOQ. The molar ratio D8F/D8E was used as a biomarker of adipose HSD-1 activity. <h3>Results</h3> Data from the 2 participants who received SPI-62 6 mg QD for 14 days, and from whom data were collected on Days 1, 2, and 14, are presented. D8F/D8E declined from baseline 90.8% and 93.5% during Day 1. D8F/D8E was on average decreased from baseline 94.2% and 95.6% during Day 2, and 92.0% and 93.9% during Day 14. <h3>Conclusion</h3> Human adipose HSD-1 activity and inhibition can be quantitated via D8E infusion of subcutaneous tissue via measurement of the molar ratio of the corresponding HSD-1 product D8F/D8E in dialysate. SPI-62 does not show tachyphylaxis on adipose HSD-1 inhibition within 14 days. A combination product of prednisolone with the HSD-1 inhibitor SPI-62 is now in a Phase 2 clinical trial as a steroid symptom sparing agent, initially for patients with polymyalgia rheumatica. The selected regimen for that trial, SPI-62 6 mg QD, is appropriate to assess clinical effects that might be associated with adipose HSD-1 inhibition. Data from all 12 participants will be used to model dose-exposure-response relationships to refine dose selection for future clinical trials. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> David Katz Shareholder of: Sparrow Pharmaceuticals, Employee of: Sparrow Pharmaceuticals, Guohua An Consultant of: Sparrow Pharmaceuticals, Caleb Schmicker: None declared, Brian Engel: None declared, Tobias Magers: None declared, Rita Basu Consultant of: Sparrow Pharmaceuticals, Julio Gutierrez: None declared.